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Kye-taek Lim - One of the best experts on this subject based on the ideXlab platform.

  • PhytoGlycoprotein isolated from Dioscorea batatas Decne promotes intestinal epithelial wound healing
    Chinese journal of natural medicines, 2020
    Co-Authors: Ji-yun Kim, Kye-taek Lim, Young-min Lee, Jong Pil Park, Sei Jung Lee
    Abstract:

    Dioscorea batatas Decne (DBD) has been used to heal various illnesses of the kidney and intestine as an herbal medicine in Asia. As a source of therapeutic agents, many Glycoproteins have been isolated from mushrooms and plants, but the functional role of Glycoprotein in intestinal epithelial wound healing has not been understood yet. In the present study, we investigated the wound healing potentials of the 30 kDa Glycoprotein (DBD Glycoprotein) isolated from DBD in human intestinal epithelial (INT-407) cells. We found that DBD Glycoprotein (100 μg·mL-1) significantly increased the motility of INT-407 cells for 24 h by activating protein kinase C (PKC). DBD Glycoprotein stimulated the activation of p38 mitogen-activated protein kinase (MAPK), which is responsible for the phosphorylation of NF-κB inhibitor α (IκBα). DBD Glycoprotein increased the level of profilin-1 (PFN1), α-actinin and F-actin expression via activation of transcription factor, nuclear factor-kappa B (NF-κB) during its promotion of cell migration. Experimental mouse colitis was induced by adding dextran sulfate sodium (DSS) to the drinking water at a concentration of 4% (W/V) for 7 days. We figured out that administration of DBD Glycoprotein (10 and 20 mg·kg-1) lowers the levels of disease activity index and histological inflammation in DSS-treated ICR mice. In this regard, we suggest that DBD Glycoprotein has ability to promote the F-actin-related migration signaling events via activation of PKC and NF-κB in intestinal epithelial cells and prevent inflammatory bowel disease.

  • CTB Glycoprotein (75kDa) inhibits IgE releasing, TNF-α and IL-6 expressed by bisphenol A in vivo and in vitro.
    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2012
    Co-Authors: Jin Lee, Sei Jung Lee, Kye-taek Lim
    Abstract:

    Cudrania tricuspidata Bureau (CTB) has been used to treat allergies and inflammatory disease as folk medicine in Korea. The objective of this study is to determine whether a Glycoprotein isolated from CTB (75 kDa) has a preventive potential of allergic inflammation caused by bisphenol A (BPA) in BALB/c mice and RBL-2H3 cells. Production of immunoglobulin (Ig) E and releasing of β-hexosaminidase and histamine at treatment of CTB Glycoprotein (5-10mg/kg, BW) were evaluated in mice serum. Activation of extracellular signal-regulated kinases (ERK) and p38 mitogen-activated protein kinase (MAPK), activator protein (AP)-1, expressions of pro-inflammatory cytokines, nitric oxide (NO) production and cyclooxygenase (COX)-2 were assessed in RBL-2H3 cells. In the results, CTB Glycoprotein (10mg/kg, BW) inhibited the production of IgE and releasing of β-hexosaminidase and histamine. Also, the CTB Glycoprotein (100 μg/ml) blocked phosphorylation of ERK1/2 and p38 MAPK, and the activation of AP-1, while it inhibited the NO production, activities of COX-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, but not IL-1β. Taken together, the results of this study indicated that the CTB Glycoprotein modulates the expression of allergic inflammation-related factors via the suppression of MAPK/AP-1 activation.

  • Inhibitory effect of plant-originated Glycoprotein (27 kDa) on expression of matrix metalloproteinase-9 in cadmium chloride-induced BNL CL.2 cells.
    Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 2011
    Co-Authors: Jin Lee, Kye-taek Lim
    Abstract:

    Abstract Cadmium is very harmful to the environment and to human beings because of its long lifetime. The toxicity of cadmium as an industrial pollutant and a food contaminant, and as one of the major components in cigarette smoke is well known. Cadmium can cause a number of lesions in many organs, such as the kidney, the lung, the liver, the brain, the blood system. However, the mechanism of toxicity of cadmium is not yet clear. Also, it has been well known as human carcinogen which is indirectly caused inflammation-mediated hepatocarcinoma. In the present study it was demonstrated that Glycoprotein (27 kDa) isolated from Gardenia jasminoides Ellis (GJE) protects BNL CL.2 cells from expression of inflammation-related factors stimulated by cadmium chloride (10 μM). Intracellular ROS and intracellular Ca2+ using fluorescence, activities of activator protein (AP)-1, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-9, and arachidonic acid (AA) using immunoblot analysis or radioactivity were evaluated. The results obtained from this experiment indicated that GJE Glycoprotein (100 μg/mL) inhibits the production of intracellular ROS, and intracellular Ca2+ mobilization. Also, it significantly suppressed inflammatory factors [expression of AP-1 (c-Jun and c-Fos), arachidonic acid, COX-2, and MMP-9]. Taken together, these findings suggest that GJE Glycoprotein might be used for protection of inflammation caused by cadmium ion as one of natural compounds.

  • Plant-originated Glycoprotein (24 kDa) has an inhibitory effect on proliferation of BNL CL.2 cells in response to di(2-ethylhexyl)phthalate.
    Cell biochemistry and function, 2011
    Co-Authors: Jin Lee, Kye-taek Lim
    Abstract:

    Di(2-ethylhexyl)phthalate (DEHP) is one of the many environmental chemicals that are widely used in polyvinyl chloride products, vinyl flooring, food packaging and infant toys. They cause cell proliferation or dysfunction of human liver. The purpose of this study is to investigate the inhibitory effect of a Glycoprotein (24 kDa) isolated from Zanthoxylum piperitum DC (ZPDC) on proliferation of liver cell in the DEHP-induced BNL CL. 2 cells. [3H]-thymidine incorporation, intracellular reactive oxygen species (ROS), intracellular Ca2+ mobilization and activity of protein kinase C (PKC) were measured using radioactivity and fluorescence method respectively. The expression of mitogen-activated protein kinases [extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK)], activator protein (AP)-1 (c-Jun and c-Fos), proliferating cell nuclear antigen (PCNA) and cell cycle-related factors (cyclin D1/cyclin-dependent kinase [CDK] 4) were evaluated using Western blotting or electrophoretic mobility shift assay. The results in this study showed that the levels of [3H]-thymidine incorporation, intracellular ROS, intracellular Ca2+ mobilization and activity of PKCα were inhibited by ZPDC Glycoprotein (100 µg/ml) in the DEHP-induced BNL CL. 2 cells. Also, activities of ERK, JNK and AP-1 were reduced by ZPDC Glycoprotein (100 µg/ml). With regard to cell proliferation, activities of PCNA and cyclin D1/CDK4 were significantly suppressed at treatment with ZPDC Glycoprotein (100 µg/ml) in the presence of DEHP. Taken together, these findings suggest that ZPDC Glycoprotein significantly normalized activities of PCNA and cyclin D1/CDK4, which relate to cell proliferation factors. Thus, ZPDC Glycoprotein appears to be one of the compounds derived from natural products that are able to inhibit cell proliferation in the phthalate-induced BNL CL. 2 cells. Copyright © 2011 John Wiley & Sons, Ltd.

  • Cudrania tricupidata bureau (CTB) Glycoprotein inhibits proliferation by Di(2-ethylhexyl) phthalate in primary splenocytes: responses in cell proliferation signaling.
    Immunological investigations, 2011
    Co-Authors: Kye-taek Lim
    Abstract:

    The aim of the present study was to evaluate inhibitory effect of CTB Glycoprotein isolated from Cudrania tricuspidata Bureau on DEHP-induced cell proliferation in lymphocytes. Our results revealed that DEHP increased lymphocyte proliferation as confirmed by increasing [3H]thymidine incorporation, and proliferating cell nuclear antigen (PCNA), cyclin D1, and cyclin-dependent kinase (CDK)-4 expression. This was accompanied by induced intracellular Ca2+ level, protein kinase C (PKC) translocation from cytosol to membrane, ERK1/2 phosphorylation, and nuclear factor (NF)-κB transcriptional activation in DEHP-treated cells. However, CTB Glycoprotein (100 μg/ml) reduced labeled thymidine incorporation and PCNA expression in DEHP-treated cells. Additionally CTB Glycoprotein reduced Ca2+ level, PKC translocation, ERK1/2 phosphorylation, NF-κB transcriptional activation, cell cycle proteins (cyclin D1 and CDK4) expression in cells. The activation of NF-κB was collectively blocked by pretreatment with PKC inhibitor...

Kwang Lim - One of the best experts on this subject based on the ideXlab platform.

  • 36 kDa Glycoprotein Isolated from Rhus verniciflua Stokes Inhibits G/GO‐Induced Mitochondrial Apoptotic Signal Pathways in BNL CL.2 Cells
    Basic & clinical pharmacology & toxicology, 2005
    Co-Authors: Sei Jung Lee, Kwang Lim, Kye-taek Lim
    Abstract:

    Abstract:Rhus verniciflua Stokes is one of the medicinal plants traditionally used to heal and treat hepatic and inflammatory diseases. We found that a Glycoprotein isolated from the fruit has a molecular weight of 36 kDa and consists of a carbohydrate component (38.75%) and a protein (61.25%), and that the Glycoprotein has a strong scavenging activity against hydroxyl radicals without any pro-oxidant activity in the cell-free system. In glucose/glucose oxidase (G/GO)-induced BNL CL.2 cells, the results showed that Rhus verniciflua Stokes Glycoprotein has dose-dependent blocking activities against G/GO-induced cytotoxicity and apoptosis, increasing the glutathione (GSH) peroxidase activity. In the activity of the mitochondrial apoptotic mediators (cytochrome c, caspases and poly(ADP-ribose)polymerase (PARP)), the Glycoprotein (100 μg/ml) showed an inhibitory effect on cytochrome c release, caspase-9/3 activation, and PARP cleavage. Moreover, Rhus verniciflua Stokes Glycoprotein has a stimulating effect on the nitric oxide production. Here, we speculate that this Glycoprotein is one of the natural antioxidants and of the modulators of apoptotic signal pathways in BNL CL.2 cells.

  • Effects of Glycoprotein isolated from Rhus verniciflua stokes on TPA-induced apoptosis and production of cytokines in cultured mouse primary splenocytes.
    Toxicology letters, 2003
    Co-Authors: Kye-taek Lim, Sei Jung Lee, Kyung-sun Heo, Kwang Lim
    Abstract:

    Abstract Glycoprotein of Rhus verniciflua Stokes (RVS Glycoprotein) was isolated and identified using SDS-PAGE. To study the anti-apoptotic effects of RVS Glycoprotein on mouse splenocytes, splenocytes were exposed to 100 nM TPA (61.68 ng/ml) for 3 h with or without RVS Glycoprotein (100 μg/ml). Results from our experiment showed that RVS Glycoprotein protects from splenocyte apoptosis induced by 12-O-tetradecanoylphorbol 13-acetate (TPA). We also studied the effects of RVS Glycoprotein on the proliferation of T/B cells and the production of cytokines. Our results showed that Concanavalin A (Con A)-induced T cell proliferation and the production of interleukin-2 (IL-2)/interleukin-4 (IL-4) were reduced, and that Lipopolysaccharide (LPS)- induced B cell proliferation and the Tumor necrosis factor alpha (TNF-α) were reduced significantly by the addition of 50 μg/ml RVS Glycoprotein (P

Sei Jung Lee - One of the best experts on this subject based on the ideXlab platform.

  • PhytoGlycoprotein isolated from Dioscorea batatas Decne promotes intestinal epithelial wound healing
    Chinese journal of natural medicines, 2020
    Co-Authors: Ji-yun Kim, Kye-taek Lim, Young-min Lee, Jong Pil Park, Sei Jung Lee
    Abstract:

    Dioscorea batatas Decne (DBD) has been used to heal various illnesses of the kidney and intestine as an herbal medicine in Asia. As a source of therapeutic agents, many Glycoproteins have been isolated from mushrooms and plants, but the functional role of Glycoprotein in intestinal epithelial wound healing has not been understood yet. In the present study, we investigated the wound healing potentials of the 30 kDa Glycoprotein (DBD Glycoprotein) isolated from DBD in human intestinal epithelial (INT-407) cells. We found that DBD Glycoprotein (100 μg·mL-1) significantly increased the motility of INT-407 cells for 24 h by activating protein kinase C (PKC). DBD Glycoprotein stimulated the activation of p38 mitogen-activated protein kinase (MAPK), which is responsible for the phosphorylation of NF-κB inhibitor α (IκBα). DBD Glycoprotein increased the level of profilin-1 (PFN1), α-actinin and F-actin expression via activation of transcription factor, nuclear factor-kappa B (NF-κB) during its promotion of cell migration. Experimental mouse colitis was induced by adding dextran sulfate sodium (DSS) to the drinking water at a concentration of 4% (W/V) for 7 days. We figured out that administration of DBD Glycoprotein (10 and 20 mg·kg-1) lowers the levels of disease activity index and histological inflammation in DSS-treated ICR mice. In this regard, we suggest that DBD Glycoprotein has ability to promote the F-actin-related migration signaling events via activation of PKC and NF-κB in intestinal epithelial cells and prevent inflammatory bowel disease.

  • CTB Glycoprotein (75kDa) inhibits IgE releasing, TNF-α and IL-6 expressed by bisphenol A in vivo and in vitro.
    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2012
    Co-Authors: Jin Lee, Sei Jung Lee, Kye-taek Lim
    Abstract:

    Cudrania tricuspidata Bureau (CTB) has been used to treat allergies and inflammatory disease as folk medicine in Korea. The objective of this study is to determine whether a Glycoprotein isolated from CTB (75 kDa) has a preventive potential of allergic inflammation caused by bisphenol A (BPA) in BALB/c mice and RBL-2H3 cells. Production of immunoglobulin (Ig) E and releasing of β-hexosaminidase and histamine at treatment of CTB Glycoprotein (5-10mg/kg, BW) were evaluated in mice serum. Activation of extracellular signal-regulated kinases (ERK) and p38 mitogen-activated protein kinase (MAPK), activator protein (AP)-1, expressions of pro-inflammatory cytokines, nitric oxide (NO) production and cyclooxygenase (COX)-2 were assessed in RBL-2H3 cells. In the results, CTB Glycoprotein (10mg/kg, BW) inhibited the production of IgE and releasing of β-hexosaminidase and histamine. Also, the CTB Glycoprotein (100 μg/ml) blocked phosphorylation of ERK1/2 and p38 MAPK, and the activation of AP-1, while it inhibited the NO production, activities of COX-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, but not IL-1β. Taken together, the results of this study indicated that the CTB Glycoprotein modulates the expression of allergic inflammation-related factors via the suppression of MAPK/AP-1 activation.

  • Hypolipidemic and Antioxidative Effects of the Plant Glycoprotein (36 kDa) from Rhus verniciflua Stokes Fruit in Triton WR-1339-Induced Hyperlipidemic Mice
    Bioscience biotechnology and biochemistry, 2006
    Co-Authors: Sei Jung Lee, Kye-taek Lim
    Abstract:

    We investigated the hypolipidemic and antioxidative effects on male ICR mice of a Glycoprotein isolated from Rhus verniciflua Stokes (RVS) fruit. The administration of the RVS Glycoprotein (100 mg/kg) for two weeks resulted in a significant decrease in such plasma lipid levels as total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL). The levels of TC, TG and LDL in the hyperlipidemic model were significantly increased, whereas the high-density lipoprotein (HDL) level was considerably decreased. The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity and the level of thiobarbituric acid-reactive substances (TBARS) were significantly elevated, whereas the production of nitric oxide (NO) was diminished. Moreover, the administration of the RVS Glycoprotein prior to inducing hyperlipidemic mice suppressed the increase in the plasma lipid levels (TC, TG and LDL), and decrease in the HDL level in Triton WR-1339-induced hyperlipidemic mice. Furthermore, the RVS Glycoprotein significantly inhibited the activity of HMG-CoA reductase and the levels of TBARS in the hyperlipidemic mice. In addition, the activities of detoxicant enzymes [catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)] were gradually augmented after a supplement with the RVS Glycoprotein. The results suggest that the RVS Glycoprotein would be effective in preventing an increase in the plasma lipid levels and in improving the antioxidant levels. This protein might be useful as a therapeutic agent.

  • 36 kDa Glycoprotein Isolated from Rhus verniciflua Stokes Inhibits G/GO‐Induced Mitochondrial Apoptotic Signal Pathways in BNL CL.2 Cells
    Basic & clinical pharmacology & toxicology, 2005
    Co-Authors: Sei Jung Lee, Kwang Lim, Kye-taek Lim
    Abstract:

    Abstract:Rhus verniciflua Stokes is one of the medicinal plants traditionally used to heal and treat hepatic and inflammatory diseases. We found that a Glycoprotein isolated from the fruit has a molecular weight of 36 kDa and consists of a carbohydrate component (38.75%) and a protein (61.25%), and that the Glycoprotein has a strong scavenging activity against hydroxyl radicals without any pro-oxidant activity in the cell-free system. In glucose/glucose oxidase (G/GO)-induced BNL CL.2 cells, the results showed that Rhus verniciflua Stokes Glycoprotein has dose-dependent blocking activities against G/GO-induced cytotoxicity and apoptosis, increasing the glutathione (GSH) peroxidase activity. In the activity of the mitochondrial apoptotic mediators (cytochrome c, caspases and poly(ADP-ribose)polymerase (PARP)), the Glycoprotein (100 μg/ml) showed an inhibitory effect on cytochrome c release, caspase-9/3 activation, and PARP cleavage. Moreover, Rhus verniciflua Stokes Glycoprotein has a stimulating effect on the nitric oxide production. Here, we speculate that this Glycoprotein is one of the natural antioxidants and of the modulators of apoptotic signal pathways in BNL CL.2 cells.

  • Effects of Glycoprotein isolated from Rhus verniciflua stokes on TPA-induced apoptosis and production of cytokines in cultured mouse primary splenocytes.
    Toxicology letters, 2003
    Co-Authors: Kye-taek Lim, Sei Jung Lee, Kyung-sun Heo, Kwang Lim
    Abstract:

    Abstract Glycoprotein of Rhus verniciflua Stokes (RVS Glycoprotein) was isolated and identified using SDS-PAGE. To study the anti-apoptotic effects of RVS Glycoprotein on mouse splenocytes, splenocytes were exposed to 100 nM TPA (61.68 ng/ml) for 3 h with or without RVS Glycoprotein (100 μg/ml). Results from our experiment showed that RVS Glycoprotein protects from splenocyte apoptosis induced by 12-O-tetradecanoylphorbol 13-acetate (TPA). We also studied the effects of RVS Glycoprotein on the proliferation of T/B cells and the production of cytokines. Our results showed that Concanavalin A (Con A)-induced T cell proliferation and the production of interleukin-2 (IL-2)/interleukin-4 (IL-4) were reduced, and that Lipopolysaccharide (LPS)- induced B cell proliferation and the Tumor necrosis factor alpha (TNF-α) were reduced significantly by the addition of 50 μg/ml RVS Glycoprotein (P

Jeffrey S. Weber - One of the best experts on this subject based on the ideXlab platform.

  • patterns of onset and resolution of immune related adverse events of special interest with ipilimumab detailed safety analysis from a phase 3 trial in patients with advanced melanoma
    Cancer, 2013
    Co-Authors: Jeffrey S. Weber, Celeste Lebbe, Reinhard Dummer, Veerle De Pril, Stephen F Hodi
    Abstract:

    BACKGROUND: Ipilimumab 3 mg/kg was the first agent to demonstrate improved survival in previously treated patients with metastatic melanoma in a phase 3 trial (MDX010-20). Ipilimumab produced a characteristic spectrum of immune-related adverse events (irAEs) of special interest, consistent with its immune-based mechanism of action. METHODS: In MDX010-20, 676 previously treated patients were randomized 3:1:1 to receive ipilimumab 3 mg/kg plus the Glycoprotein 100 melanoma antigen vaccine (gp100), ipilimumab 3 mg/kg + placebo, or gp100 vaccine + placebo. For the current report, the authors conducted a detailed analysis of the time to onset and resolution of irAEs associated with ipilimumab therapy. RESULTS: Grade 2 through 5 irAEs generally developed during the induction phase of treatment (0-12 weeks). Most, including grade 3/4 irAEs, were reversible when managed with treatment guidelines using vigilant monitoring and corticosteroids. The median time to resolution (to grade 1 or 0 or to the grade at baseline) of irAEs that had an onset during the induction phase was approximately 6 weeks for grade 2 through 4 irAEs and 8 weeks for grade 3 and 4 irAEs. Across the entire study duration, most grade 2 through 4 irAEs resolved within 12 weeks. CONCLUSIONS: Most ipilimumab-associated irAEs, including grade 3/4 symptoms, developed within 12 weeks of initial dosing and resolved within 12 weeks of onset. IrAEs were well characterized in their evolution and could be managed using published algorithms. Cancer 2013. © 2013 American Cancer Society.

  • ipilimumab plus dacarbazine for previously untreated metastatic melanoma
    The New England Journal of Medicine, 2011
    Co-Authors: Caroline Robert, Jeffrey S. Weber, Luc Thomas, Igor Bondarenko, Claus Garbe, Celeste Lebbe, Jean Francois Baurain, Alessandro Testori, Steven J Oday, Jean Jacques Grob
    Abstract:

    A B S T R AC T Background Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with Glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. Methods We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Results Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab–dacarbazine group. Conclusions Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.)

  • Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma
    The New England journal of medicine, 2011
    Co-Authors: Caroline Robert, Jeffrey S. Weber, Steven J. O'day, Luc Thomas, Igor Bondarenko, Claus Garbe, Celeste Lebbe, Jean Francois Baurain, Alessandro Testori, Jean Jacques Grob
    Abstract:

    A B S T R AC T Background Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with Glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. Methods We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Results Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P

  • programmed death 1 blockade enhances expansion and functional capacity of human melanoma antigen specific ctls
    International Immunology, 2007
    Co-Authors: Raymond M Wong, Ron R Scotland, Alan J. Korman, W. Martin Kast, Changyu Wang, Jeffrey S. Weber
    Abstract:

    Negative co-stimulatory signaling mediated via cell surface programmed death (PD)-1 expression modulates T and B cell activation and is involved in maintaining peripheral tolerance. In this study, we examined the effects of a fully human PD-1-abrogating antibody on the in vitro expansion and function of human vaccine-induced CD81 T cells (CTLs) specific for the melanoma-associated antigens Glycoprotein 100 (gp100) and melanoma antigen recognized by T cells (MART)-1. PD-1 blockade during peptide stimulation augmented the absolute numbers of CD31, CD41, CD81 and gp100/MART-1 MHC:peptide tetramer1 CTLs. This correlated with increased frequencies of IFN-gsecreting antigen-specific cells and augmented lysis of gp1001/MART-11 melanoma targets. PD-1 blockade also increased the fraction of antigen-specific CTLs that recognized melanoma targets by degranulation, suggesting increased recognition efficiency for cognate peptide. The increased frequencies and absolute numbers of antigen-specific CTLs by PD-1 blockade resulted from augmented proliferation, not decreased apoptosis. Kinetic analysis of cytokine secretion demonstrated that PD-1 blockade increased both type-1 and type-2 cytokine accumulation in culture without any apparent skewing of the cytokine repertoire. These findings have implications for developing new cancer immunotherapy strategies.

Caroline Robert - One of the best experts on this subject based on the ideXlab platform.

  • ipilimumab plus dacarbazine for previously untreated metastatic melanoma
    The New England Journal of Medicine, 2011
    Co-Authors: Caroline Robert, Jeffrey S. Weber, Luc Thomas, Igor Bondarenko, Claus Garbe, Celeste Lebbe, Jean Francois Baurain, Alessandro Testori, Steven J Oday, Jean Jacques Grob
    Abstract:

    A B S T R AC T Background Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with Glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. Methods We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Results Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab–dacarbazine group. Conclusions Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.)

  • Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma
    The New England journal of medicine, 2011
    Co-Authors: Caroline Robert, Jeffrey S. Weber, Steven J. O'day, Luc Thomas, Igor Bondarenko, Claus Garbe, Celeste Lebbe, Jean Francois Baurain, Alessandro Testori, Jean Jacques Grob
    Abstract:

    A B S T R AC T Background Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with Glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. Methods We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Results Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P

  • improved survival with ipilimumab in patients with metastatic melanoma
    The New England Journal of Medicine, 2010
    Co-Authors: Stephen F Hodi, David F. Mcdermott, Jeffrey A. Sosman, John B. A. G. Haanen, Rene Gonzalez, Caroline Robert, Dirk Schadendorf, Steven J Oday, R Weber, Jessica C. Hassel
    Abstract:

    Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a Glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

  • Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.
    The New England journal of medicine, 2010
    Co-Authors: F. Stephen Hodi, Steven J. O'day, David F. Mcdermott, R. W. Weber, Jeffrey A. Sosman, John B. A. G. Haanen, Rene Gonzalez, Caroline Robert, Dirk Schadendorf, Jessica C. Hassel
    Abstract:

    Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a Glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P